title: Divergence of IL-1, IL-18, and cell death  in NLRP3 inflammasomopathies.
abstract: The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1-mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.
authors.forename: Susannah D
authors.initials: SD
authors.lastname: Brydges
authors.forename: Lori
authors.initials: L
authors.lastname: Broderick
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.forename: Carla A
authors.initials: CA
authors.lastname: Pena
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000097:blood; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000097:blood; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics; D053724:Receptors, Interleukin-18 / Q000172:deficiency / Q000235:genetics; D012867:Skin / Q000276:immunology / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D050505:Mutant Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D020170:Caspase 1